Overall Freshly ejaculated mammalian sperm are unable to fertilize an egg. They acquire fertilizing capacity in the hours following ejaculation, as they pass through the female reproductive tract, in a process known as capacitation. Soluble adenylyl cyclase (sAC: ADCY10) is a non-hormonal target essential for sperm capacitation and male fertility. Pharmacological sAC inhibitors block sperm functions in vitro and two distinct sAC knockout (KO) mouse strains exhibit male-specific sterility without exhibiting other overt phenotypes. This proposed Contraception Research Center (CRC) has a singular scientific theme; to identify the safest and most efficacious means for blocking sAC in vivo to achieve an on-demand contraceptive pill. The overall design of the CRC leverages the already successful interdisciplinary team comprised of expertise in sAC pharmacology and biochemistry (Drs. Levin & Buck), sAC structural biology (Dr. Steegborn), and medicinal chemistry and drug development [Dr. Meinke & his team at the Tri-Institutional Therapeutics Discovery Institute (TDI)]. To complete the CRC, we add to this team an Andrology Core (led by Drs. Lamb & Schlegel) for assessing efficacy against human sperm. In the first two Projects, we focus on sAC catalytic domain inhibitors with the expectation that pharmacokinetic parameters can be optimized to balance efficacy with minimal adverse effects. In the first project, we will perform in vivo studies of efficacy, safety, and pharmacokinetics to refine the existing scaffold of sAC inhibitors with proven efficacy in mice into preclinical development candidates suitable for development partners to apply for an FDA Investigational New Drug (IND). The goal of Project 2 is to develop additional leads, based upon recombination and optimization of moieties from distinct, but structurally and biochemically validated scaffolds, which would be suitable for subjecting to the in vivo studies proposed in Project 1. The third project proposes a high throughput screening strategy to identify inhibitors targeting regulatory domains of sAC isoforms enriched in sperm. Such inhibitors should exhibit diminished side effects. The ultimate goal of Project 3 is to identify hits which will be developed using the same principles and methods outlined in Projects 1 and 2. The overall hypothesis tested in this CRC is that sAC inhibitors can be designed which can be appropriately dosed to block sperm functions while minimizing undesirable side effects.